The international, multi-site Colon Cancer Family Registry has established a cohort of approximately 37,000 colorectal cancer cases and their relatives, who are at increased risk of colorectal and other cancers, from over 10,000 families from the USA, Canada, Australia and New Zealand. Existing standardized data from members include baseline epidemiologic and follow-up questionnaires, clinical data, blood/buccal samples, tumor blocks, comprehensive genotype data, including genome-wide association study (GWAS) data on all population-based case- and control-probands, extensive molecular characterization of the colorectal tumors, and genetic characterization of participants for the cancer predisposing Lynch syndrome. All participants have been asked to participate in 5-yearly follow-up, and with an 87% participation, have contributed a total of 390,000 person- life years and 759 incident colorectal and 3,554 incident other cancers. The resource has been used for 420 publications (143 in the past project period) and 304 projects (73 in the past project period). In this application, we seek funding for continued support of the cohort infrastructure, to continue follow-up of participants, and to enhance the cohort with innovative characterization of value to future research on the prevention, aetiology and prognosis of CRC. We propose the following specific aims: Aim 1: Maintain the cohort by active follow-up of participants and maintenance of the biorepository. Aim 2: Characterize incident cancers including: diagnosis and treatment records, pathology reports, collection of blocks, pathology review of tumors, mismatch repair status of tumors, and genotyping participants for Lynch syndrome and MUTYH. Aim 3: Enhance the cohort in three ways: a) measuring the immune cell contexture in colorectal carcinoma; b) test cohort participants for inherited mutations in recently discovered colorectal cancer susceptibility genes; and c) derive individual risk of future colorectal cancer for all cohort members based on their questionnaire, molecular, clinical and genomic data. Aim 4: Preserve, and encourage continued utilization of the Colon Cancer Family Registry Cohort and its resources through active collaborations with the larger scientific community. Maintaining and enhancing our core infrastructure will facilitate our broad research agenda and will ensure that the Colon Cancer Family Registry Cohort is increasingly valuable to research science and ultimately the public's health.